Synaptic transmission between neurons of the enteric nervous system (ENS) is crucial for the exquisite coordination of the gastrointestinal tract that is required for the motility of luminal substances in the aboral direction. It is the amplitude of individual fast excitatory postsynaptic potentials (fEPSPs) that determines if the postsynaptic cell reaches threshold and fires an action potential. We have found that individual fEPSPs are augmented in the inflamed colon, and determining the mechanisms contributing to fast synaptic facilitation is the goal of this grant application, since this can lead to the dysmotility found in inflammatory bowel disease (IBO). The hypothesis to be tested is that synaptic facilitation in the myenteric plexus of the inflamed colon is due to a change in the presynaptic neurotransmitter release mechanism, and is induced by the inflammatory mediators, nitric oxide, interferon gamma, and/or tumor necrosis factor alpha. Specific aim 1 will test whether this is due to a change in calcium sensitivity and probability of release of neurotransmitter that leads to this facilitation, specific aim 2 will test if it is due to an increase in synaptic density that leads to this facilitation, and specific aim 3 will test the potential roles of cytokines and nitric oxide. [unreadable] [unreadable] [unreadable]